Has been published in March 2015 on Canadian Journal of Emergency Medicine (CJEM), the Canadian Association of Emergency Physicians Position Statement on Acute Ischemic Stroke.

Let’s see what they say about thrombolitic therapy and administration timing.

THROMBOLYTIC THERAPY WITHIN 3 HOURS OF STROKE SYMPTOM ONSET

Summary of Evidence

Seven trials either specifically addressed the efficacy of rt-PA in stroke within three hours of symptom onset or provided data on a subgroup of patients receiving therapy within three hours of symptom onset.

Fibrinolytic therapy administered within three hours of symptom onset increases the probability of survival with a favourable neurologic outcome (NNT 10).

This favourable effect appears to be independent of age, including patients aged 80 and older.

Pooled data from several clinical trials suggest an important relationship between time from symptom onset to treatment and outcome. Patients treated with rt-PA within 90 minutes to symptom onset were more likely to have a favourable neurologic outcome compared to those treated from 90 – 180 minutes to treatment onset.

Recommendations

1. Patients with acute ischemic stroke whose neuroimaging excludes contraindications, and who can be treated within three hours of symptom onset, should be offered rt-PA with the goal of improving functional outcome (STRONG RECOMMENDATION, HIGH QUALITY EVIDENCE)

2. Stroke patients meeting eligibility criteria for thrombolytic therapy should be treated as rapidly as possible, with a target door-to-needle time of less than 60 minutes (STRONG RECOMMENDATION, MODERATE QUALITY EVIDENCE)

3. Due to limited resources and practical constraints, the administration of thrombolytic therapy within 3 hours in rural hospital may not be feasible and hence not recommended in all of these settings but should fall to the discretion of the local decision making team(WEAK RECOMMENDATION, LOW QUALITY EVIDENCE)

MEDEST COMMENT:

The statement is fair enough. The 3 hrs time window, even with the controversy that all the 7 available studies evidenced, is pretty condivisible. I love the great emphasis on ” target door-to-needle time of less than 60 minutes” that has to be the real target of all Emergency Systems. Is also well thought the flexibility on rural hospital and the assumption that treatment in those situations is discretional. Very well done i feel to subscribe everything!

THROMBOLYTIC THERAPY WITHIN 3—4.5 HOURS OF STROKE SYMPTOM ONSET

Summary of Evidence

A pooled analysis of all trials involving acute ischemic stroke patients treated in the 3.0 to 4.5 hour time window was published by Emberson et al. in 2014. Combing data from 7 studies that included 2768 patients, the likelihood of a favorable outcome was higher if patients were randomized to rt-PA. (Emberson J, Lees KR, Lyden P, et al; for the StrokeThrombolysis Trialists’ Collaborative Group. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014;384(9958):1929-35)(.……) the latter figure (of the meta-analysis) showing significant imprecision and no difference in mortality, but a direction of effect towards a mortality increase with rt-PA in a dose-response relationship between time to treatment and 90-day mortality, suggesting a potential for increased mortality in those treated beyond 3 hours.

Included in this most recent systematic review is patient-level data from the IST-3 trial.

IST-3 suggested a 7-fold increase in symptomatic ICH associated with thrombolytic use (7% vs. 1%) as well as an expected increase in early mortality but no difference in disability or mortality at 6 months for those treated at 3–4.5 hours.

Recommendations

1. Thrombolytic therapy for acute ischemic stroke patients should not be routinely offered for the treatment of acute ischemic stroke for patients if administered beyond three hours of stroke symptom onset (WEAK RECOMMENDATION, MODERATE QUALITY EVIDENCE).

2. The administration of thrombolytic therapy for acute ischemic stroke beyond 3 hours from stroke symptom onset should be restricted to specialized stroke centers with advanced imaging capabilities or as part of a research protocol (WEAK RECOMMENDATION, LOW QUALITY EVIDENCE).

MEDEST COMMENT:

Even for this part of the statement my agreement is total.IST 3 that is, at the moment, the largest study on thrombolytic therapy for ischemic stroke is a total contradiction in terms of evidence about benefit and major bleeding events.Good outcome in the first 3 hrs, a majority of adverse events between 3 and 4,5 hrs and again beneficial between 4,5 and 6 hrs. Just one consideration: the results are not suitable for clinical practice.So “Thrombolytic therapy for acute ischemic stroke patients should not be routinely offered for the treatment of acute ischemic stroke for patients if administered beyond three hours of stroke symptom onset“.

This is in contrast with the 2013 AHA/ASA Guidelines for the Early Management of Patients With Acute Ischemic Stroke that states:

Intravenous rtPA (0.9 mg/kg, maximum dose 90 mg) is recommended for administration to eligible patients who can be treated in the time period of 3 to 4.5 hours after stroke onset (Class I; Level of Evidence B). The eligibility criteria for treatment in this time period are similar to those for people treated at earlier time periods within 3 hours, with the following additional exclusion criteria: patients >80 years old, those taking oral anticoagulants regardless of INR, those with a baseline NIHSS score >25, those with imaging evidence of ischemic injury involving more than one third of the MCA territory, or those with a history of both stroke and diabetes mellitus.

Bottom line:

I really like this Statement and think that is one of best available policy about thrombolytic therapy and ischemic stroke.